The immunophilins are a class of molecules implicated in a variety of functions, most notably immunoregulation. Immunophilins are the protein receptors for the potent immunosuppressive drugs cyclosporin A, FK506, and rapamycin. These drugs are used to prevent graft rejection and to treat autoimmune disorders. There are two major classes of these immunophilins: the cyclosporin A binding proteins, designated cyclophilins, and the FK506 binding proteins (FKBPs). Although they have related functions, these two groups lack structural and sequence homology.
The cyclophilin/cyclosporin A complex and the FKBP/FK506 complex apparently accomplish immunosuppression by blocking the Ca+2/calmodulin-dependent serine/threonine protein phosphatase activity of calcineurin, an enzyme that supposedly plays a role in the signal transduction pathway leading to translocation of certain transcription factors from the cytosol to the nucleus of mammalian T cells. Inhibition of the phosphatase activity of calcineurin appears to block T cell activation and inhibits T cell lymphokine production. Specifically, cyclosporin A and FK506 inhibit expression of IL-2, IL-3, IL-4, GM-CSF, TNF-alpha, gamma-interferon, and other nonlymphokine genes (e.g. IL-2R). Rapamycin is structurally similar to FK506 but suppresses T cell activation at a different level, mainly through inhibition of proliferation induced by lymphokines.
In addition to their immunosuppressive functions, the immunophilins have peptidyl-prolyl cis-trans isomerase activity (also sometimes referred to as rotamase activity). This activity is putatively unrelated to immunosuppression. Additionally, there is some suggestion that the immunophilins can act as an ATP-independent chaperone protein, facilitating the folding of target proteins and the assembly of multisubunit protein complexes (see Price et al., Proc. Natl. Acad. Sci. 91:3931 (1994); Freskgard et al., Science 258:466 (1992)), although this activity is unclear (Kern et al., FEBS Letters 348:145 (1994)).
The cyclophilins are apparently ubiquitous throughout nature, and the sequences of more than 27 cyclophilins and 17 FKBPs are known. Sequence alignment of the cyclophilin sequences reveals two "signature" sequences which are present in almost all of the cyclophilins (see Trandinh et al., FASEB J. 6:3410 (1992). In addition, the position corresponding to residue 121 in human cyclophilin A has been implicated in strong cyclosporin binding (see Liu et al., Biochem. 30:2306-2310 (1991)). The E. coli cyclophilins, which bind poorly to cyclosporin, have a phenylalanine at this position; when this residue is mutated to tryptophan, the isomerase activity becomes more sensitive to cyclosporin.
Finally, only a few of the native cyclophilin substrates are known, most notably Drosophila rhodopsin and HIV-1 Gag (see Luban et al., Cell 73:1067-78 (1993); Stamnes et al., Cell 65:219-227 (1991)). Accordingly, the actual mechanisms and processes by which the cyclophilins effect their regulatory mechanisms are not yet elucidated.